Cocaine use is associated with a number of cardiovascular complications including acute myocardial infarction, arrhythmias, and stroke. The mechanism(s) of cocaine-induced cardiovascular toxicity are poorly understood. Most cocaine users co-ingest ethanol which is reported to enhance the euphoric and decrease the dysphoric effects of cocaine. Simultaneous use of these two drugs results in formation of the pharmacologically active cocaine metabolite, cocaethylene. Cocaethylene is frequently found in the blood and urine of patients suffering cocaine- related morbidity and mortality in concentrations up to twice that of cocaine. Recent studies in humans reported co-administration of ethanol and cocaine significantly increased the magnitude and duration of cocaine's cardiovascular effects. These findings indicate ethanol may play an important role in the pathogenesis of cocaine-induced cardiac toxicity. Whether the enhanced cardiac effects were due to increased cocaine plasma concentrations from inhibition of cocaine's metabolism (by either ethanol or cocaethylene) or to the cardiovascular actions of cocaethylene is unclear. The long-term goal of this project is to gain a better understanding of the interaction between cocaine and ethanol in cocaine users. In this proposal, studies are planned using the conscious dog model to evaluate the cocaine-ethanol interaction. The overall hypothesis to be evaluated is that, in the presence of ethanol, the cardiovascular effects of cocaine are increased by: (1) inhibition of cocaine's metabolism by ethanol or cocaethylene resulting in higher cocaine plasma concentrations, or (2) the cardiovascular actions of cocaethylene. The first aim seeks to characterize cocaine pharmacokinetics and cardiovascular response in the presence and absence of cocaethylene. Comparison of cocaine's clearance and concentration- effect relationships will identify whether a pharmacokinetic or pharmacodynamic interaction exists. The second aim will compare the pharmacokinetics and cardiovascular response to cocaine and cocaethylene in the presence and absence of ethanol. These studies will reveal if the mechanism of enhanced cardiac effects of cocaine in the presence of ethanol is due to either inhibition of cocaine's metabolism, cardiovascular effects of cocaethylene, or cardiovascular effects of ethanol. The results of the present stud will provide insight into the role of ethanol in the cardiovascular toxicity of cocaine and lead to improved understanding of the mechanisms of cocaine-induced cardiac complications.